tbuckley/cabot-search huggingface dataset:
KS01.7.A ADAPTOR FITC CAR T-CELLS AND OCTO-FLUO ELICIT PROMISING ANTITUMOR ACTIVITY IN MENINGIOMA VIA SSTR2
Authors: J Chen, C Pellegrino, M Mastall, L Padevit, N Favalli, G Bassi, M Neidert, F Vasella, P Roth, D Neri, M Manz, M Weller, H Wirsching
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Effective treatment options for meningioma patients beyond surgical resection and radiotherapy are lacking. Somatostatin receptor (SSTR) 2 is expressed by most meningiomas. Here, we report pre-clinical and translational evidence for the activity of an SSTR2-targeted adaptor CAR T cell system in meningiomas. MATERIAL AND METHODS Tissue microarrays of meningioma (N=384) patient samples stained for SSTR2. Fluorescein-linked, octameric cyclic peptide SSTR2 antagonist OCTO-FLUO (kindly provided by Philogen, Otelfingen, Switzerland). Adaptor FITC CAR T-cells generated by lentiviral transduction of healthy donor T-cells. Flow cytometry-based killing assays in vitro in SSTR2-expressing meningioma (Ben-Men-1 IOMM-Lee) cells, and ex vivo utilizing freshly dissociated surgical meningioma specimens, by co-incubation with OCTO-FLUO and adaptor FITC CAR T-cells. Orthotopic growth and mouse survival following subdural implantation of IOMM-Lee cells, genetically engineered to express luciferase, i.v. treated with OCTO-FLUO and intratumoral injection of CAR T-cells. RESULTS SSTR2 expression was overall heterogeneous and was high or intermediate in most World Health Organization (WHO) grade 2 (87.8 %) or grade 3 (87.5 %) meningiomas. In vitro, 10 nM was determined as the optimal concentration of OCTO-FLUO, yielding tumor cell killing within 72 hours at effector-target cell (ET) ratios as low as 1:100 in Ben-Men-1 (CAR vs untransduced T-cells [UTT] 47.9 % vs 4.7 %, p &amp;lt; 0.001) and IOMM-Lee (CAR vs UTT 40.2 % vs 4.9 %, p &amp;lt; 0.001) cells. Tumor growth inhibition by the adaptor FITC CAR T-cell system in vivo was confined to SSTR2 expressing cells and was paralleled by prolonged survival compared to UTT in IOMM-Lee (hazard ratio [95% confidence interval], 0.3 [0.1 - 0.9], p=0.030). Preliminary ex vivo killing assays employing freshly dissociated patient samples yielded specific lysis-rates in the range of 15-20% (ET 1:1) at 12 hours. Updated ex vivo results employing optimized protocols will be presented at the conference. CONCLUSION Targeting SSTR2 positive meningioma cells with an adaptor FITC CAR T-cell system is feasible. Syngeneic murine models and the use of adaptor molecules directed against murine SSTR2 will be required to explore secondary immune reactions and off-tumor effects prior to proceeding to early phase clinical trials.
JS05.7.A SURGICAL RE-RESECTION FOR RECURRENT GLIOBLASTOMA: PROGNOSTIC EVALUATION USING THE NOVEL RANO CLASSIFICATION FOR EXTENT OF RESECTION FROM THE RANO<i>RESECT</i> GROUP
Authors: P Karschnia, A Dono, J S Young, S T Juenger, N Teske, L Häni, T Sciortino, C Y Mau, F Bruno, L Nunez, R A Morshed, A F Haddad, M Weller, M van den Bent, J Beck, S Hervey-Jumper, A M Molinaro, N Tandon, R Rudà, M A Vogelbaum, L Bello, O Schnell, S J Grau, S M Chang, M S Berger, Y Esquenazi, J Tonn
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The value of re-resection in recurrent glioblastoma remains controversial as a randomized trial that specifies intentional incomplete resection cannot be justified ethically. Here, we aimed to (I) explore the prognostic role of extent of re-resection using the previously proposed RANO classification (based upon residual contrast-enhancing (CE) and non-CE tumor), and to (II) define factors consolidating the surgical effects on outcome. MATERIAL AND METHODS The RANO resect group retrospectively compiled a global, eight-center cohort of patients with first recurrence from previously resected glioblastomas. The combined associations of re-resection and other clinical factors with outcome were analyzed. Kaplan-Meier survival analysis and log-rank test were applied to calculate survival, and Cox’s proportional hazard regression models to adjust for multiple variables (significance level: p ≤ 0.05). Propensity score-matched analyses were constructed to mimic randomized clinical trials comparing the different RANO classes. RESULTS We studied 681 with first recurrence of IDH-wildtype glioblastomas, including 310 patients who underwent re-resection. Re-resection was associated with prolonged survival even when stratifying for clinical and molecular confounders on multivariate analysis (HR for re-resection: 0.65, CI: 0.5-0.8; p = 0.001); and ≤1 cm3 residual CE tumor was associated with longer survival than non-surgical management. Accordingly, ‘maximal CE resection’ (class 2) had superior survival compared to ‘submaximal CE resection’ (class 3) (median OS after recurrence: 12 vs. 9 months; p = 0.003). Administration of (radio-)chemotherapy further augmented the survival associations of smaller residual CE tumor. The prognostic role of residual CE tumor was confirmed in propensity score analyses. Conversely, ‘supramaximal CE resection’ targeting also non-CE tumor (class 1) was not associated with prolonged survival but frequently accompanied by post-operative deficits, hampering further adjuvant treatment. CONCLUSION The RANO resect classification serves to stratify patients with re-resection of glioblastoma. Complete CE resection according to RANO resect class 1 and 2 is prognostic of outcome. The beneficial effects of re-resection might be consolidated by (radio-)chemotherapy, and avoidance of post-operative deficits hampering such treatment is of critical importance.
OS05.5.A NOVEL STUDY OF COGNITIVE REHABILITATION IMPROVING WORK PERFORMANCE IN PRIMARY BRAIN TUMOR
Authors: C Weyer Jamora, M Brie, P Bracci, E Smith, T Luks, S Phan, R Alomomen, S Braunstein, J Rottering, N Oberheim Bush, N Butowski, J Clarke, M Daras, J de Groot, S Chang, S Hervey-Jumper, J W Taylor, J W Taylor
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Primary brain cancer survivors are living longer yet have emotional distress and cognitive impairments that negatively impact their quality of life (QOL), including returning to work. We present a novel tele-cognitive rehabilitation study in primary brain cancer survivors to improve work performance. MATERIAL AND METHODS Retrospective review of clinically and radiologically stable adult primary brain cancer patients off treatment and referred for cognitive rehabilitation. Neuropsychological, psychological, vocational, and QOL assessments completed. Wilcoxon rank sum and Fisher’s exact or Chi-square tests were used for between and within-group comparisons. Work status improvement defined as returning to employment and/or minimal cognitive symptoms at work. RESULTS 79 patients with known baseline work status were analyzed. 80% opted in tele-cognitive rehabilitation services. Working (n=38), not working (n=41) had similar age, time since diagnosis, and history of radiotherapy. Not working had higher grade tumors (p=.01), worse cognitive function (executive function, attention, verbal learning all p&amp;lt;0.05) yet more engagement support groups (p&amp;lt;0.04). Subsequently, 38 patients (42% of whom were not working) received vocational tele-cognitive rehabilitation (median 11 sessions). 82% had improved work status compared to 34% non-treatment. Occupational improvements are not correlated to baseline work status and age. Glioblastoma was least improved, while Oligodendroglioma was most likely to improve (p=.05). Higher doses of radiotherapy were inversely related to work improvements (p&amp;lt;0.05). Higher verbal memory (p=0.05), processing speed (p=0.06), and executive functioning (p=0.02), IDH mutant tumors (p=0.06), and motivation for treatment (p=0.04) were associated with improved work status. Those with depressive symptoms who engaged in psychotherapeutic services had significantly improved work status (p=0.01). CONCLUSION When offered, patients want cognitive rehabilitation. Further, occupational functioning improves with tele-cognitive rehabilitation. Higher cognitive functioning, IDH mutation, radiotherapy dose, and motivation for treatment are important to consider. Despite not working and having worse cognition, patients improved similarly to their working counterparts. Depression benefitted from psychotherapeutic support. Tele-cognitive rehabilitation embedded within a multidisciplinary care model shows promise to improve work abilities in primary brain tumor patients.
Multivalent antigen display on nanoparticle immunogens increases B cell clonotype diversity and neutralization breadth to pneumoviruses
Authors: Sebastian Ols, Klara Lenart, Rodrigo Arcoverde Cerveira, Marcos C. Miranda, Natalie Brunette, Jana Kochmann, Martin Corcoran, Rebecca Skotheim, Annika Philomin, Alberto Cagigi, Brooke Fiala, Samuel Wrenn, Jessica Marcandalli, Fredrika Hellgren, Elizabeth A. Thompson, Ang Lin, Florian Gegenfurtner, Azad Kumar, Man Chen, Ganesh E. Phad, Barney S. Graham, Laurent Perez, Andrew J. Borst, Gunilla B. Karlsson Hedestam, Tracy J. Ruckwardt, Neil P. King, Karin Loré
Journal: Immunity (2023)

Nanoparticles for multivalent display and delivery of vaccine antigens have emerged as a promising avenue for enhancing B cell responses to protein subunit vaccines. Here, we evaluated B cell responses in rhesus macaques immunized with prefusion-stabilized respiratory syncytial virus (RSV) F glycoprotein trimer compared with nanoparticles displaying 10 or 20 copies of the same antigen. We show that multivalent display skews antibody specificities and drives epitope-focusing of responding B cells. Antibody cloning and repertoire sequencing revealed that focusing was driven by the expansion of clonally distinct B cells through recruitment of diverse precursors. We identified two antibody lineages that developed either ultrapotent neutralization or pneumovirus cross-neutralization from precursor B cells with low initial affinity for the RSV-F immunogen. This suggests that increased avidity by multivalent display facilitates the activation and recruitment of these cells. Diversification of the B cell response by multivalent nanoparticle immunogens has broad implications for vaccine design.
P11.73.B COMPARING GAMMA KNIFE RADIOSURGERY WITH MICROSURGERY AND THEIR RISK-BENEFIT-RATIO OF TUMOR CONTROL AND FACIAL DETERIORATION IN LARGE VESTIBULAR SCHWANNOMAS (KOOS III-IV)
Authors: S Wang, F Ebner, A Rizk, A van Eck, G Horstmann, M Tatagiba, G Naros
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The level of evidence to provide treatment recommendations for vestibular schwannoma (VS) is low. Both stereotactic radiosurgery (SRS) and microsurgical resection (SURGERY) are available as treatment options for VS. If treated with monotherapy alone, SRS has shown to be inferior in tumor control, but superior in facial nerve preservation compared to SURGERY. The aim of this study was to analyze the risk-benefit-ratio in the treatment of large VS (Koos III-IV) comparing SRS and SURGERY. MATERIAL AND METHODS This is a retrospective dual-center cohort study enrolling consecutive patients with solitaryVS between 2005 und 2011 to enable follow-up of up to 10 years. Tumor size was classified by Koos Classification. Clinical state was reported by House and Brackmann (H&amp;B) and Gardner-Robertson (G&amp;R) scale (with H&amp;B and G&amp;R 1-2 considered as good outcome), and Recurrence-free-survival (RFS) was assessed radiographically by contrast-enhanced MR imaging. As an expression of success/harm, the absolute risk reduction (ARR) and risk increase (ARI) were calculated as the difference between incidence of recurrences and facial deterioration rates in patients treated with SRS and SURGERY, respectively. ARR and ARI were used to derive additional estimates of treatment effectiveness (in SURGERY), i.e. the number-to-operate (NNO) and the number-to-harm (NNH), respectively. RESULTS The study population included N=901 patients, who were treated in both centers. N=492 (55%) were large VS (Koos III-IV). Of them N=260 (53%) were treated with SRS and N=232 (47%) with SURG. The SRS treatment arm presented with a recurrence rate of 14.2%, and SURGERY with 3.0%. Therefore, ARR for recurrence was 11.21% (95% CI: 6.4%-16.0%) with a NNO of 9 (95% CI: 6.3-15.6) in SURGERY meaning that one in every 9 patients will benefit from SURGERY treatment. When analyzing facial nerve deterioration (facial paresis HB&amp;gt;2 and facial spasm) in large VS, SRS presented with 6.9%, and SURGERY with 12.5% adverse facial nerve outcome resulting in an ARI of 5.6% (95%CI: 0.3%-10.8%) and a NNH of 18 (95%CI:9.2-312.1). CONCLUSION The analysis of the different proportion in success/harm in the management of large VS (SRS vs. SURGERY) in this cohort yielded in a low NNO, combined with a high NNH. This shows that SURGERY was superior to SRS considering tumor control in large VS (Koos III-IV). Still, the direct translation of these results into treatment recommendations is not self-evident, but multi-faceted: This analysis is a vivid representation of a dilemma well-known to neuro-oncological surgeons - the negotiation between tumor control and functional outcome. Large VS should be treated in specialized centers, which have enough experience to ensure a high-rate of facial preservation in large VS (Koos III-IV).
P10.29.A FUNCTIONALLY INSTRUCTED COMBINATION-TREATMENTS INVOLVING REGORAFENIB IN EXPERIMENTAL GLIOMA
Authors: L A Haeusser, L Kuhlburger, B Walter, H Becker, D J Merk, G Tabatabai
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma are incurable primary tumors of the central nervous system. The standard of care for newly diagnosed glioblastoma outside clinical trials includes a combination of radiation therapy, alkylating chemotherapy and tumor-treating fields. Yet, for progressive glioblastoma, only lomustine is registered in Europe. The REGOMA trial (Lombardi et al., Lancet Oncol 2019) had investigated regorafenib versus lomustine in a phase 2-trial. Furthermore, the use of regorafenib in a compassionate-use-program was recently reported (Tzaridis et al., Neuro Oncol 2019) Yet, the regorafenib arm in the Glioblastoma Adaptive Global Innovative Learning Environment (GBM Agile) master protocol was stopped after an interim analysis that showed a low probability of improvement of overall survival compared with control (press release 21 September 2022). We investigated here a functional genomics-based approach to discover and validate potential modulators of response to regorafenib treatment in experimental glioma in vitro, in vivo and ex vivo. MATERIAL AND METHODS We performed CRISPR/Cas9 activation (Calabrese P65-HSF activation library) and knockout (genome-wide knockout library Brunello) screens during treatment with regorafenib, sequenced and analyzed the genomic DNA of the remaining cells. RESULTS We discovered functionally-instructed molecular hits, designed a drug library for further validation by functional assays in vitro and combination treatments in murine glioma models in vivo. CONCLUSION Taken together, we discovered and validated functionally-instructed combination treatment options involving regorafenib. Our finalized results will be presented.
OS05.6.A TELEMEDICINE IN NEURO-ONCOLOGY - AN EVALUATION OF REMOTE CONSULTATIONS DURING THE COVID-19 PANDEMIC
Authors: J Feldheim, T Schmidt, C Oster, J Feldheim, U Sure, C Kleinschnitz, L Lazaridis, S Kebir, M Glas
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND To minimize the risk of infections during the Covid-19 pandemic, remote video consultations (VC) experienced an upswing in most medical fields. However, despite its multiple benefits, telemedicine in neuro-oncology comprises unique challenges and opportunities: Comprehensive neurological examinations that might not translate sufficiently to VC are very relevant for neuro-oncological patients. Also, communication in neuro-oncology can be highly emotional and challenging on a personal level, and VC have been accused of creating emotional distance between the patients and doctors. So far, evidence-based insights to evaluate and potentially customize current concepts of VC in neuro-oncology are scarce. MATERIAL AND METHODS We analyzed &amp;gt;3.700 neuro-oncological consultations conducted at our institution between the 1st of April 2020 and the 30th of June 2021, of which &amp;gt;300 were conducted as VC by patients' preference. Then we collected patients' basic demographic and clinical data and compared how the collective of patients that chose to participate in VC distinguished from those who did not. Also, we examined the reasons, suitable/less suitable encounters, VC's benefits and disadvantages and future opportunities by conducting an anonymized survey in the VC collective. RESULTS The ratio of VC participation correlated with the incidence of SARS-CoV-2 infections (r=0.5, p=0.03). Patients that participated in VC had worse clinical conditions and higher grades of malignancy, were more often diagnosed with glioblastoma, and had a longer travel distance (all p&amp;lt;0.01). VC were considered a fully adequate alternative to face-to-face consultations for almost all encounters that patients chose to participate in (&amp;gt;70%), except initial consultations. Most participants preferred to alternate between both modalities rather than participate in one alone but preferred VC over telephone consultation. Patients stated that VC made them feel safer. Participants also expressed interest in implementing other telemedicine modalities (e.g. apps) into neuro-oncology. CONCLUSION VC are a promising addition to patient care in neuro-oncology. However, patients and encounters should be selected individually. Patient subgroups that might be especially suitable for VC are patients with long travel distances seeking an expert opinion, patients in poor clinical condition, glioblastoma patients and patients requiring frequent consultations in person. A strength of face-to-face consultations is the more intense personal contact, whereas VC convince with a lower expense. VC made patients feel safer, and participants expressed their interest in expanding the offer of telemedicine in neuro-oncology further.
P14.11.B A MULTICENTER STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND WITH SYSTEMIC MICROBUBBLE OSCILLATORS FOR BLOOD-BRAIN BARRIER DISRUPTION FOR LIQUID BIOPSY IN GLIOBLASTOMA (LIBERATE)
Authors: M S Ahluwalia, J DeGroot, J Lee, A Mogilner, T Schwartz, T Burns, B Shah, M McDermott, C Bettegowda, A Ozair, A A Khosla, A Sahgal, M Mishra, A Achrol, N Lipsman, G Woodworth
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) levels in blood due to the blood-brain barrier (BBB). This results in challenges to the identification of blood-based biomarkers and the development of novel biomarker-driven systemic therapies. Real-time image-guided low intensity focused ultrasound (LIFU) combined with intravenously administered microbubble oscillators non-invasively causes BBB disruption (BBBD). This clinical trial aimed to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM. METHODS LIBERATE is a prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating the safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged 18-80 years with suspected GBM planned for tumor biopsy or resection at ten centers in the US are being included. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered intravenous oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using a 220 kHz LIFU device is performed with real-time acoustic feedback for effective cavitation. Before and after the procedure, phlebotomies and MRI brain are performed to evaluate outcomes. The primary study endpoint is defined, per subject, as the ratio between their cfDNA level in blood 1-hour post-LIFU procedure compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to a ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in cfDNA sample from 1-hour post-LIFU sample and biomarker pattern in tumor tissue obtained later. The trial has been powered to evaluate both primary and secondary hypotheses. Based on an assumed true agreement rate of 91% and a one-sided alpha of 0.025, an exact test for binomial proportions provides a sample of N=50 with 84% power for the secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels post-LIFU in samples collected at 30 minutes, 1 hour, 2 hours, and 3 hours to determine the time of greatest yield, (3) correlation of MRI parameters related to grading of BBBD and biomarkers positive in cfDNA from post-LIFU blood samples. RESULTS Patient enrollment commenced in 2022, and 8 patients have been recruited by 04/11/2023. CONCLUSION Findings from this trial will be critical to liquid biopsy in GBM (Clinical trial information: NCT05383872).
KS03.6.A HIGH RATE OF MULTIFOCAL RELAPSE AND SUBSEQUENT POOR PROGRESSION-FREE SURVIVAL POST SALVAGE RADIATION THERAPY FOR WHO GRADE 2-3 MENINGIOMA MANAGED WITH INITIAL SURGERY ALONE
Authors: M Back, P Horsley, J Yim, J Drummond
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Optimal initial management for patients with localised high risk meningioma remains uncertain with long natural history disease promoting the option of delaying adjuvant radiation therapy until relapse. This study assessed patterns of relapse and survival in a cohort of patients with high-risk meningioma managed with initial surgical therapy alone. MATERIAL AND METHODS Consecutive patients with meningioma referred for radiation therapy (IMRT) between January 2008-December 2021 were entered into an ethics approved database managed by the Neuro-oncology MDT. Categorisation and subsequent management plans were based by grade on WHO2007-2016 classification. Immediate or delayed referral pathway for IMRT was individualised by neurosurgical team. At time of subsequent referral for IMRT at relapse patients had tumour site / volume determined by MRI and Dotatate PET. Tumour volume, site of relapse in relation to initial cavity and number of recurrent foci of disease were recorded. For patients subsequently receiving IMRT an integrated-boost, generally 60Gy/54Gy, was used. Primary endpoints were site of relapse in relation to initial surgical cavity, number of foci, and median time from initial surgery. Secondary endpoints were median progression-free(mRFS)/overall survival(mOS) calculated from start salvage IMRT compared to cohort of intercurrent patients managed at initial diagnosis. RESULTS One hundred and five patients with meningioma were referred, with median follow-up for survivors of 3.6yrs (q1-3:1.5-7.7yrs). Median age was 59.2yrs; 59% had convexity meningioma; WHO2016 grade was G3 in 21%; Atypical(G2) in 66% and G1/no biopsy in 9% of patients. Twenty-two patients have subsequently relapsed post IMRT; with sixteen deceased for 8yrPFS and 8yrOS of 63.5% and 73.5% respectively. Forty-nine(46%) of patients were referred for IMRT at relapse, of which 39% had repeat resection prior to IMRT referral; and 14% were WHO2016 G3 at most recent resection. Based on MRI/Dotatate 61% had more than one focus of tumour around initial surgical cavity. Subsequent to salvage IMRT, fifteen of the 49 patients have had further relapse and eleven are deceased. Patients managed at relapse had worse PFS with 55.1% 8yrPFS vs 78.0% 8yrPFS (p=0.03); however equivalent OS with 68.8% 8yrOS vs 79.4% 8yrOS (p=0.62). CONCLUSION Patients with G2/3 meningioma managed with surgery alone upfront more often had relapses that were multifocal that were not managed with further salvage surgery. The subsequent progression-free survival was poor with a high rate of subsequent relapse post salvage IMRT, especially when compared to patients managed with IMRT at time of initial diagnosis.